Promoting collateral formation in type 2 diabetes mellitus using ultra-small nanodots with autophagy activation and ROS scavenging.

BACKGROUND: Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS2 NDs) for enhancing collateral formation and improving prognosis. RESULTS: Our study shows that MoS2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H2O2, •O2-, and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells. CONCLUSIONS: Overall, this study investigated the specific mechanism by which MoS2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential.

Molybdenum-Copper Antagonism In Metalloenzymes And Anti-Copper Therapy.

The connection between 3d (Cu) and 4d (Mo) via the "Mo-S-Cu" unit is called Mo-Cu antagonism. Biology offers case studies of such interactions in metalloproteins such as Mo/Cu-CO Dehydrogenases (Mo/Cu-CODH), and Mo/Cu Orange Protein (Mo/Cu-ORP). The CODH significantly maintains the CO level in the atmosphere below the toxic level by converting it to non-toxic CO2 for respiring organisms. Several models were synthesized to understand the structure-function relationship of these native enzymes. However, this interaction was first observed in ruminants, and they convert molybdate (MoO4 2- ) into tetrathiomolybdate (MoS4 2- ; TTM), reacting with cellular Cu to yield biological unavailable Mo/S/Cu cluster, then developing Cu-deficiency diseases. These findings inspire the use of TTM as a Cu-sequester drug, especially for treating Cu-dependent human diseases such as Wilson diseases (WD) and cancer. It is well known that a balanced Cu homeostasis is essential for a wide range of biological processes, but negative consequence leads to cell toxicity. Therefore, this review aims to connect the Mo-Cu antagonism in metalloproteins and anti-copper therapy.

Photothermal antibacterial MoS2 composited chitosan hydrogel for infectious wound healing.

Pathological bacterial infection poses a serious threat to public health security. The excessive use of antibiotics has resulted in a serious decline in treatment effect and bacterial resistance. For the treatment of infected wounds, we compounded dopamine-assisted exfoliated molybdenum disulfide (MoS2@PDA) into lipoic acid modified chitosan (LAMC) to obtain a composite hydrogel dressing (LAMC-MoS2@PDA). LAMC-MoS2@PDA hydrogels exhibited excellent photothermal conversion ability and the LAMC-MoS2@PDA2 group (0.3 wt%) has a photothermal conversion efficiency of 26.29 %. Meanwhile, they showed good biocompatibility and ROS scavenging activity in vitro. Photothermal therapy usually utilizes photothermal agents to convert near-infrared light into heat energy for bacterial cell membrane destruction and bacterial protein inactivation. Under the near-infrared light irradiation, the antibacterial ratio of LAMC-MoS2@PDA hydrogels against Staphylococcus aureus and Escherichia coli reached nearly 100 %, and the morphology of the bacteria showed obvious contraction and cleavage. The hydrogels also showed an excellent antibacterial effect and wound healing promotion in the infected wound of rats. In particular, the LAMC-MoS2@PDA2 (+) group (with NIR) showed almost complete wound closure after 14 days, indicating that the LAMC-MoS2@PDA hydrogels have great potential in clinical anti-infected treatment.

Molybdenum nanoparticles as a potential topical medication for alopecia treatment through antioxidant pathways that differ from minoxidil.

BACKGROUND: Hair loss is a common dermatological condition including various types such as alopecia areata, androgenetic alopecia, etc. Minoxidil is a topical medication used for treating hair loss, which is effective for various types of alopecia. However, minoxidil has limitations in treating hair loss, such as slow onset of action and low efficacy, and it cannot effectively inhibit one of the major pathogenic factors of hair loss - excessive oxidative stress. METHODS: Transition metal elements with rapid electron transfer, such as molybdenum, have been extensively studied and applied for inhibiting oxidative stress. We established a mouse model for hair growth and intervened with nano-sized molybdenum, minoxidil, and a combination of both. The physicochemical properties of nano-sized molybdenum enabled it to mediate oxidative stress more quickly. RESULTS: The results showed that nano-sized molybdenum can accelerate hair growth, increase the number of local hair follicles, and reduce the expression of oxidative stress-related molecules such as iNOS, COX2, and androgen receptors. The combination of nano-sized molybdenum and minoxidil showed an additive effect in promoting hair growth. CONCLUSION: Our findings suggest that nano-sized molybdenum might be a potential topical medication for treating hair loss by inhibiting the oxidative stress pathway. Nano-sized molybdenum, alone or in combination with minoxidil, could be a promising therapeutic approach for patients with hair loss, particularly those who do not respond well to current treatments. Further clinical studies are warranted to confirm the efficacy and safety of this novel treatment.

Molybdenum Nanodots for Acute Lung Injury Therapy.

Acute respiratory disease syndrome (ARDS) is a common critical disease with high morbidity and mortality rates, yet specific and effective treatments for it are currently lacking. ARDS was especially apparent and rampant during the COVID-19 pandemic. Excess reactive oxygen species (ROS) production and an uncontrolled inflammatory response play a critical role in the disease progression of ARDS. Herein, we developed molybdenum nanodots (MNDs) as a functional nanomaterial with ultrasmall size, good biocompatibility, and excellent ROS scavenging ability for the treatment of acute lung injury (ALI). MNDs, which were administered intratracheally, significantly ameliorated lung oxidative stress, inflammatory response, protein permeability, and histological severity in ALI mice without inducing any safety issues. Importantly, transcriptomics analysis indicated that MNDs protected lung tissues by inhibiting the activation of the Nod-like receptor protein 3 (NLRP3)-dependent pyroptotic pathway. This work presents a promising therapeutic agent for patients suffering from ARDS.

All-in-One Engineering Multifunctional Nanoplatforms for Sensitizing Tumor Low-Temperature Photothermal Therapy In Vivo.

Low-temperature photothermal therapy (PTT) is a noninvasive method that harnesses the photothermal effect at low temperatures to selectively eliminate tumor cells, while safeguarding normal tissues, minimizing thermal damage, and enhancing treatment safety. First we evaluated the transcriptome of tumor cells at the gene level following low-temperature treatment and observed significant enrichment of genes involved in cell cycle and heat response-related signaling pathways. To address this challenge, we have developed an engineering multifunctional nanoplatform that offered an all-in-one strategy for efficient sensitization of low-temperature PTT. Specifically, we utilized MoS2 nanoparticles as the photothermal core to generate low temperature (40-48 °C). The nanoplatform was coated with DPA to load CPT-11 and Fe2+ and was further modified with PEG and iRGD to enhance tumor specificity (MoS2/Fe@CPT-11-PEG-iRGD). Laser- and acid-triggered release of CPT-11 can significantly increase intracellular H2O2 content, cooperate with Fe2+ ions to increase intracellular lipid ROS content, and activate ferroptosis. Furthermore, CPT-11 induced cell cycle arrest in the temperature-sensitive S-phase, and increased lipid ROS levels contributed to the degradation of HSPs protein expression. This synergistic approach could effectively induce tumor cell death by the sensitized low-temperature PTT and the combination of ferroptosis and chemotherapy. Our nanoplatform can also maximize tumor cell eradication and prolong the survival time of tumor-bearing mice in vivo. The multifunctional approach will provide more possibilities for clinical applications of low-temperature PTT and potential avenues for the development of multiple tumor treatments.

Biometals in Alzheimer disease: emerging therapeutic and diagnostic potential of molybdenum and iodine.

The current ageing trend of the world population has, in part, accounted for Alzheimer disease (AD) being a public health issue in recent times. Although some progress has been made in clarifying AD-related pathophysiological mechanisms, effective intervention is still elusive. Biometals are indispensable to normal physiological functions of the human body-for example, neurogenesis and metabolism. However, their association with AD remains highly controversial. Copper (Cu) and zinc (Zn) are biometals that have been investigated at great length in relation to neurodegeneration, whereas less attention has been afforded to other trace biometals, such as molybdenum (Mo), and iodine. Given the above context, we reviewed the limited number of studies that have evidenced various effects following the usage of these two biometals in different investigative models of AD. Revisiting these biometals via thorough investigations, along with their biological mechanisms may present a solid foundation for not only the development of effective interventions, but also as diagnostic agents for AD.

NIR-responsive molybdenum (Mo)-based nanoclusters enhance ROS scavenging for osteoarthritis therapy.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorders globally, and treating OA remains a significant challenge. Currently, pharmacological treatments primarily aim to alleviate the OA symptoms associated with inflammation and pain, and no disease-modifying therapies are available to delay OA development and progression. Reactive oxygen species (ROS) play an essential role in OA development and progression, which are a promising target for curing OA. In this study, it was found that photothermal properties of near-infrared (NIR) irradiation enhanced the ROS scavenging activity of molybdenum-based polyoxometalate (POM) nanoclusters. Because of enhanced ROS scavenging, NIR-responsive POM nanoclusters were developed as novel excellent nano-antioxidants for OA protection. The results demonstrated that NIR-responsive POM exhibited outstanding antioxidant activity and superexcellent anti-inflammatory effects, which could effectively alleviate the clinical symptoms of OA mice, diminish inflammatory cytokines, reduce catabolic proteases, and mitigate the progression of OA. Meanwhile, the local treatment had no side effects on normal tissues. Thus, this study pioneered the application of POM for alleviating OA with expected safety and efficiency.

Z-scheme MoS2/Co3S4@PEG nanoflowers: Intracellular NIR-II photocatalytic O2 production facilitating hypoxic tumor therapy.

Intratumoral hypoxia, which is in favour of cancer cell proliferation, invasion and metastasis, also inhibits photodynamic therapy (PDT) badly. Herein, second near-infrared (NIR-II) photocatalytic O2 production is established to realize hypoxia relief. MoS2/Co3S4@PEG (MSCs@PEG) nanoflowers (100-150 nm) are prepared via a two-step hydrothermal method. These samples possess high NIR-II harvest and photothermal conversion (39.8 %, 1064 nm) ability. That not only reveals photothermal therapy (PTT) but also lifts the thermal energy of nanomaterials to replenish extra energy, making sure the co-excitation of MoS2 (1.14 eV) and Co3S4 (1.40 eV) by low-energy NIR-II (1064 nm, 1.16 eV) laser. The investigation of band structure further displays the Z-Scheme characterization of MSCs heterostructure. These photo-excited holes/electrons hold great redox ability to form O2 (water splitting) and reactive oxygen species (ROS), simultaneously. In addition, MSC-2@PEG can be served to mimic catalase, peroxidase, and glutathione (GSH) oxidase to further boost oxidative stress. It is noted that heterostructure discovers the greater nanozyme activity, attributing to the lower resistance for charge transfer. Moreover, MSC-2@PEG displays a novel biodegradation ability to induce the elimination via urine and faeces within 14 days. Given the superparamagnetic and photothermal effect, the nanocomposite can be used as magnetic resonance and photothermal imaging (MRI and PTI) contrast. Associated with dual-imaging, intracellular O2 supplementation, and synergistic chemotherapy (CDT)/PTT/PDT, MSC-2@PEG possess great tumor inhibition that also efficiently motivates immune response for anticancer.

Oral zero-valent-molybdenum nanodots for inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) affects millions of people each year. The overproduction of reactive oxygen species (ROS) plays a critical role in the progress of IBD and will be a potential therapeutic target. Here, we synthesize a kind of oral zero-valent-molybdenum nanodots (ZVMNs) for the treatment of IBD by scavenging ROS. These ultrasmall ZVMNs can successfully pass through the gastric acid and then be absorbed by the intestine. It has been verified that ZVMNs can down-regulate the quantity of ROS and reduce colitis in a mouse IBD model without distinct side effects. In addition, RNA sequencing reveals a further mechanism that the ZVMNs can protect colon tissues from oxidative stress by inhibiting the nuclear factor κB signaling pathway and reducing the production of excessive pro-inflammatory factors. Together, the ZVMNs will offer a promising alternative treatment option for patients suffering from IBD.

Molybdenum-Iodine Cluster Loaded Polymeric Nanoparticles Allowing a Coupled Therapeutic Action with Low Side Toxicity for Treatment of Ovarian Cancer.

The ability of cancer cells to develop resistance to anti-cancer drugs, known as multidrug resistance, remains a major cause of tumor recurrence and cancer metastasis. This work explores the double mechanism of toxicity of (D, L-lactide-co-glycolide) acid (PLGA) nanoparticles encapsulating a molybdenum cluster compound, namely Cs2[{Mo6I8}(OOCC2F5)6] (CMIF). Hemocompatibility and biocompatibility assays show the safe potential of CMIF loaded nanoparticles (CNPs) as delivery systems intended for tumor targeting for PDT of ovarian cancer with a slight hemolytic activity and a lack of toxicity up to 50 µM CMIF concentration. Cellular uptake shows a preferential uptake of CNPs in lysosomes, which is not interfering with CMIF activity. The double mechanism of CNPs consists in a production of ROS and a DNA damage activity, from 5 µM and 0.5 µM respectively (CMIF concentration). The cellular death mechanism comprises 80% of necrosis and 20% of direct apoptosis by direct DNA damages. This work confirms CMIF loaded PLGA nanoparticles as an efficient and relevant delivery system for PDT.

Confined Construction of Ultrasmall Molybdenum Disulfide-Loaded Porous Silica Particles for Efficient Tumor Therapy.

Recently, molybdenum sulfide (MoS2) has shown great application potential in tumor treatment because of its good photothermal properties. Unfortunately, most of the current molybdenum disulfide-based nanotherapeutic agents suffer from complex preparation processes, low photothermal conversion efficiencies, and poor structural/compositional regulation. To address these issues, in this paper, a facile "confined solvothermal" method is proposed to construct an MoS2-loaded porous silica nanosystem (designated as MoS2@P-hSiO2). The maximum photothermal efficiency of 79.5% of molybdenum-based materials reported in the literature at present was obtained due to the ultrasmall MoS2 nanoclusters and the rich porous channels. Furthermore, both in vitro and in vivo experiments showed that the cascade hybrid system (MoS2/GOD@P-hSiO2) after efficient loading of glucose oxidase (GOD) displayed a significant tumor-suppressive effect and good biosafety through the combined effects of photothermal and enzyme-mediated cascade catalytic therapy. Consequently, this hybrid porous network system combining the in situ solvothermal strategy of inorganic functional components and the efficient encapsulation of organic enzyme macromolecules can provide a new pathway to construct synergistic agents for the efficient and safe treatment of tumors.

Differential Efficacy of B-Ultrasound Combined with Molybdenum Target Detection Mode for Breast Cancer Staging and Correlation of Blood Flow Parameters with IGF-1 and IGF-2 Expression Level and Prognosis.

The study investigates the diagnostic efficacy of ultrasound combined with the molybdenum target mode in breast cancer staging and the relationship between blood flow parameters and the expression of insulin-like growth factor 1 (IGF-1) and factor 2 (IGF-2) and prognosis. A total of 96 patients admitted to hospital from January 2020 to January 2021 are included in the breast cancer group, and 58 patients admitted to our hospital during the same period are included in the control group, who are diagnosed with benign breast lesions. All patients receive clinicopathological diagnosis, ultrasound detection, and X-ray molybdenum detection. Ultrasound detection, molybdenum target detection, ultrasound combined with the molybdenum target detection mode, and clinicopathological diagnosis results are compared. B-ultrasound combined with the molybdenum target detection mode has high efficiency in diagnosing breast cancer and differentiating pathological stages. Besides, blood flow parameters of patients are closely related to IGF-1 and IGF-2, and IGF-1 and IGF-2 expressions are closely related to the prognosis of patients. Subsequent diagnosis of the disease degree of breast cancer patients can be carried out by ultrasound combined with the molybdenum target detection mode. In addition, the expression of IGF-1 and IGF-2 in patients can be monitored to improve the clinical diagnosis and treatment plan to improve the prognosis of patients, which has a high clinical application value and is worth promoting.

Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer.

Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS2) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS2 has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (L-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS2 (MoS2-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8+ cells in the tumor and promotes CD8+ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS2-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS2-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8+) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC.

Conducting molybdenum sulfide/graphene oxide/polyvinyl alcohol nanocomposite hydrogel for repairing spinal cord injury.

A sort of composite hydrogel with good biocompatibility, suppleness, high conductivity, and anti-inflammatory activity based on polyvinyl alcohol (PVA) and molybdenum sulfide/graphene oxide (MoS2/GO) nanomaterial has been developed for spinal cord injury (SCI) restoration. The developed (MoS2/GO/PVA) hydrogel exhibits excellent mechanical properties, outstanding electronic conductivity, and inflammation attenuation activity. It can promote neural stem cells into neurons differentiation as well as inhibit the astrocytes development in vitro. In addition, the composite hydrogel shows a high anti-inflammatory effect. After implantation of the composite hydrogel in mice, it could activate the endogenous regeneration of the spinal cord and inhibit the activation of glial cells in the injured area, thus resulting in the recovery of locomotor function. Overall, our work provides a new sort of hydrogels for SCI reparation, which shows great promise for improving the dilemma in SCI therapy.

Tumor acidity and near-infrared light responsive drug delivery MoS2-based nanoparticles for chemo-photothermal therapy.

The rational design of tumor microenvironment (TME)- multifunctional stimuli-responsive nanocomposites is appealing for effective cancer treatment. However, multidrug resistance remains an obstacle to construct responsive oncotherapy. Herein, a novel MoS2/PDA-TPP nanocomposite loaded with chemotherapy drug of doxorubicin (DOX) is designed for TME dual-response and synergistically enhanced anti-tumor therapy based on the tumor-specific mitochondria accumulation ability and photothermal (PTT) therapy. In detail, the designed MoS2/PDA-TPP nanoplatform can act as a pH-responsive dissociation to endow fast release of DOX under an acidic TME and simultaneously improve the efficiency of PTT. Moreover, the mechanism shows that MoS2/PDA-TPP trigger mitochondrial-dependent apoptosis by producing reactive oxygen species (ROS) and reducing mitochondrial membrane potential (MMP). Most importantly, during PTT procedure, hyperthermia up to 50 °C can effectively induce tumor cell death without causing severe inflammation to adjacent tissues. Tumor targeting double stimulation response of nanocomposites is a novel idea to overcome drug resistance, which will provide a more effective strategy for solving practical problems.

Antiproliferative and antiangiogenic effects of ammonium tetrathiomolybdate in a model of endometriosis.

AIMS: Copper (Cu) is involved in the endometriosis progression. Herein, an experimental endometriosis model was used to evaluate whether its chelation with ammonium tetrathiomolybdate (TM) affects the proliferation and angiogenesis in endometriotic-like lesions and the participation of oxidative stress in these processes. MAIN METHODS: Female C57BL/6 mice were divided into three groups: sham-operated mice, endometriosis-induced mice, and TM-treated endometriosis-induced mice. Each animal in the third group received 0.3 mg of TM/day in their drinking water from the postoperative 15th day. The samples were collected after one month of induced pathology. In peritoneal fluids, Cu and estradiol levels were determined by electrothermal atomic absorption spectrometry and electrochemiluminescence, respectively. Endometriotic-like lesions were processed for the analysis of cell proliferation by PCNA immunohistochemistry, the expression of angiogenic markers by RT-qPCR, the presence of endothelial cells by immunofluorescent staining, and oxidative stress applying spectrophotometric methods. KEY FINDINGS: TM treatment decreased Cu and estradiol levels, which were increased by this pathology. In lesions, TM induced: (a) a decrease in tissue weight and volume, (b) a decrease in PCNA-positive cells, (c) antiangiogenic effects by decreasing the number of blood vessels, the mRNA expression of fibroblast growth factor 2 (Fgf2) and platelet-derived growth factor subunit B (Pdgfb), and the presence of endothelial cells, (d) a decrease in antioxidant activity and an increase in lipid peroxidation. SIGNIFICANCE: TM is a highly effective antiproliferative and antiangiogenic agent, modulating oxidative imbalance in endometriosis. Its anti-endometriotic potential is an attractive feature of TM as a possible non-hormonal treatment.

Transition-Metal Dichalcogenide Artificial Antibodies with Multivalent Polymeric Recognition Phases for Rapid Detection and Inactivation of Pathogens.

Antibodies are recognition molecules that can bind to diverse targets ranging from pathogens to small analytes with high binding affinity and specificity, making them widely employed for sensing and therapy. However, antibodies have limitations of low stability, long production time, short shelf life, and high cost. Here, we report a facile approach for the design of luminescent artificial antibodies with nonbiological polymeric recognition phases for the sensitive detection, rapid identification, and effective inactivation of pathogenic bacteria. Transition-metal dichalcogenide (TMD) nanosheets with a neutral dextran phase at the interfaces selectively recognized S. aureus, whereas the nanosheets bearing a carboxymethylated dextran phase selectively recognized E. coli O157:H7 with high binding affinity. The bacterial binding sites recognized by the artificial antibodies were thoroughly identified by experiments and molecular dynamics simulations, revealing the significance of their multivalent interactions with the bacterial membrane components for selective recognition. The luminescent WS2 artificial antibodies could rapidly detect the bacteria at a single copy from human serum without any purification and amplification. Moreover, the MoSe2 artificial antibodies selectively killed the pathogenic bacteria in the wounds of infected mice under light irradiation, leading to effective wound healing. This work demonstrates the potential of TMD artificial antibodies as an alternative to antibodies for sensing and therapy.

Nerve Growth Factor-Targeted Molecular Theranostics Based on Molybdenum Disulfide Nanosheet-Coated Gold Nanorods (MoS2-AuNR) for Osteoarthritis Pain.

Osteoarthritis (OA) is a leading cause of chronic pain in the elderly worldwide. Yet current diagnosis and therapy for OA pain are subjective and nonspecific with significant adverse effects. Here, we introduced a theranostic nanoprobe based on molybdenum disulfide nanosheet-coated gold nanorods (MoS2-AuNR) targeting never growth factor (NGF), a key player in pain sensation, for photoacoustic pain imaging and near-infrared (NIR) imaging-guided photothermal analgesic therapy. MoS2 coating significantly improved the photoacoustic and photothermal performance of AuNR. Functionalization of MoS2-AuNR nanoprobes by conjugating with NGF antibody enabled active targeting on painful OA knees in a surgical OA murine model. We observed that our functional nanoprobes accumulated in the OA knee rather than the contralateral intact one, and the amount was correlated with the severity of mechanical allodynia in our mouse model. Under imaging guidance, NIR-excited photothermal therapy could mitigate mechanical allodynia and walking imbalance behavior for both subacute and chronic stages of OA in a preclinical setting. This molecular theranostic approach enabled us to specifically localize the source of OA pain and efficiently block peripheral pain transmission.